The immune system has evolved to provide an organism with a flexible and dynamic mechanism to respond specifically to a wide variety of antigenic insults. In order for an immune response to occur following antigenic challenge, the antigen must not only be recognized by antigen specific lymphocytes, but this recognition event must lead to a variety of cellular responses. T lymphocytes, together with B lymphocytes, represent the two antigen specific components of the cellular immune system. T cells are central to the immune response and control the response to infectious agents, tumors and transplants.
The T cell receptor for antigen (TCR) recognizes and binds foreign antigens. This binding event leads to T cell activation. The activation of T lymphocytes is a complex process which results in cell growth and differentiation. The engagement of the TCR on mature peripheral T cells initiates multiple intracellular signals that can lead to cellular proliferation and the acquisition of complex effector functions.
The biochemical mechanisms that couple receptor binding to these intracellular events have been intensively investigated. Early events such as activation of tyrosine phosphorylation, elevation of intracellular calcium, activation of lipid-dependent kinases, and activation of Ras and its downstream kinase cascade are well known [Weiss, A. and Littman, D. R., Signal transduction by lymphocyte antigen receptors, Cell 76:263-274 (1994); Cantrell, D., T Cell Antigen Receptor Signal Transduction Pathways, Annu. Rev. Immunol., 14:259-274 (1996)]. Moreover, there has been analysis of the events involved in transcriptional induction of T cell-specific lymphokines. There remain, however, significant gaps in the understanding of TCR signaling, particularly in how the early tyrosine phosphorylation events couple receptor activation to later cellular events.
Perhaps the most critical insight of the past decade in the study of signal transduction has been the recognition that activation of receptor tyrosine kinases results in the assembly of multimolecular complexes at the cytoplasmic domain of the receptor. Likewise, a major role of the tyrosine phosphorylation cascade initiated by TCR engagement is the assembly of multimolecular signaling complexes at and near the TCR itself. The identity and functions of these proteins that engage in such molecular interactions, are critical in the understanding of T cell receptor signal transduction.